Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of terminal liver diseases including liver cirrhosis and hepatocellular carcinoma. Growing evidence demonstrates the critical importance of inflammation in the pathogenesis of NAFLD. For instance, nutrient overload triggers inflammation, which can act through stimulating lipogenesis to increase hepatic steatosis. The latter, in turn, can exacerbate liver inflammation and progress to non-alcoholic steatohepatitis (NASH). However, the precise mechanisms underlying the interaction between hepatic steatosis and liver inflammation remain to be elucidated. Thus, the long-term goal of the proposed research is to dissect the metabolic and inflammatory mechanisms underlying NAFLD in order that novel evidence-based approaches can be developed for preventing and/or treating NASH. As a G-protein-coupled receptor, adenosine 2A receptor (A2AR) is abundantly expressed in immune cells and exhibits powerful anti-inflammatory properties. A2AR is also highly expressed in hepatocytes, in which A2AR functions are largely unknown. For this project, the central hypothesis is that the A2AR in hepatocytes and macrophages protects against the development of different aspects of NAFLD in a cell-type-dependent manner. This hypothesis is based on the following novel findings: 1) A2AR deficiency in hepatocytes plays a more important role than A2AR deficiency in myeloid cells (macrophages) in exacerbating high-fat diet (HFD)- induced hepatic steatosis, which is associated with increased hepatic expression of lipogenic enzymes; 2) A2AR deficiency exacerbates HFD-induced liver inflammation, which is likely attributed to increased macrophage/Kupffer cell proinflammatory activation; and 3) A2AR activation by a specific agonist protects mice from HFD-induced NAFLD. Thus, the goal of this project is to define a novel protective role for A2AR in NAFLD. For this purpose, mice that lack A2AR in hepatocytes and/or myeloid cells are generated.
For Specific Aim 1, in vivo experiments will be performed to examine the extent to which the A2AR in hepatocytes acts through inhibiting lipogenesis to protect against NAFLD. Moreover, cellular experiments will be performed to elucidate the involvement of SREBP1c and ChREBP in A2AR inhibition of lipogenic gene expression.
For Specific Aim 2, in vivo experiments will be performed to examine the extent to which the A2AR in macrophages or hepatocytes protects against NAFLD by suppressing liver inflammatory response.
For Specific Aim 3, in vivo experiments will be performed to define A2AR coordination of hepatocyte-macrophage crosstalk in NAFLD. Moreover, in vitro co-culture experiments will be performed to examine the extent to which factors generated by A2AR-deficient macrophages, i.e., TNF? and IL-6, stimulate hepatocyte lipogenesis, and the extent to which factors generated by A2AR-deficient hepatocytes, i.e., palmitate, stimulate macrophage proinflammatory activation. Together, the proposed research will illustrate a new paradigm on NAFLD, and provide the experimental basis for prevention and/or treatment of NASH by means of A2AR activation.
Results from the proposed research will significantly advance the knowledge of the pathophysiology of NAFLD. Furthermore, the successful completion of this project will support the development of A2AR-based novel approaches for preventing and/or treating NASH, for which no effective treatment is currently available.
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